U.S. patent application number 09/821846 was filed with the patent office on 2002-01-31 for synthesis of thiazolium compounds.
Invention is credited to Wagle, Dilip.
Application Number | 20020013471 09/821846 |
Document ID | / |
Family ID | 22711353 |
Filed Date | 2002-01-31 |
United States Patent
Application |
20020013471 |
Kind Code |
A1 |
Wagle, Dilip |
January 31, 2002 |
Synthesis of thiazolium compounds
Abstract
Provided is a method of synthesizing a compound of formula I, 1
comprising: (a) reacting a compound of formula II 2 wherein R.sub.1
and R.sub.2 are independently hydrogen,
hydroxy(C.sub.1-C.sub.2)alkyl, or (C.sub.1-C.sub.2)alkyl with, a
compound of formula III 3 wherein R.sub.3, R.sub.4, and R.sub.5 are
each independently of each other hydrogen, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)alkoxy, or halogen; and X is a leaving group, in a
solvent having a dielectric constant at 20.degree. C. of at least
30 but no more than 40; and (b) obtaining the compound I.
Inventors: |
Wagle, Dilip; (New York,
NY) |
Correspondence
Address: |
DECHERT
P.O. Box 5218
Princeton
NJ
08543
US
|
Family ID: |
22711353 |
Appl. No.: |
09/821846 |
Filed: |
March 29, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60192867 |
Mar 29, 2000 |
|
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Current U.S.
Class: |
548/204 |
Current CPC
Class: |
C07D 277/22
20130101 |
Class at
Publication: |
548/204 |
International
Class: |
C07D 277/12 |
Claims
What is claimed:
1. A method of synthesizing a compound of formula I, 8comprising:
(a) reacting a compound of formula II 9wherein R.sub.1 and R.sub.2
are independently hydrogen, hydroxy(C.sub.1-C.sub.2)alkyl, or
(C.sub.1-C.sub.2)alkyl with, a compound of formula III 10wherein
R.sub.3, R.sub.4, and R.sub.5 are each independently of each other
hydrogen, (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alokxy, or
halogen; and X is a leaving group, in a solvent having a dielectric
constant at 20.degree. C. of at least 30 but no more than 40; and
(b) obtaining the compound of formula I.
2. The method of claim 1, wherein the amount of solvent is selected
to dissolve compounds II and III, but precipitate at least a
portion of the compound of formula I during the reacting step.
3. The method of claim 2, wherein the amount of solvent is selected
to precipitate an amount of the compound I equal to at least 20% of
the theoretical yield.
4. The method of claim 1, wherein the solvent is aprotic.
5. The method of claim 1, wherein the solvent is acetonitrile.
6. The method of claim 1, wherein the reacting step is conducted at
elevated temperatures maintained for at least 24 hours.
7. The method of claim 1, wherein the reacting step is conducted at
reflux.
8. The method of claim 1, further comprising: (c) re-crystallizing
the product; (d) washing the re-crystallized product by suspending
it in a mixture of a C.sub.1 to C.sub.3 alcohol and a C.sub.3 to
C.sub.5 ether; and (e) recovering the product, wherein the
alcohol/ether mixture, time of suspension, and an election to
conduct a total of one to three iterations of steps (d) and (e) are
selected to achieve at least 95% yield from the crystallized
product of step (c) and a purity of at least 99.5% by isocratic,
reversed-phase HPLC analysis monitored at 210 nm.
9. The method of claim 8, wherein the re-crystallized product is
suspended in a mixture of ethanol and methyl tert-butyl ether.
10. The method of claim 9, wherein the mixture is a 2:8 to 4:6
(v/v) mixture, respectively.
11. The method of claim 10, wherein the mixture is a 25:75 to 35:65
(v/v) mixture
12. The method of claim 1, further comprising: (c) re-crystallizing
the product; (d.sup.1) washing the re-crystallized product by
suspending it in a 2:8 to 4:6 (v/v) mixture of a C.sub.1 to C.sub.3
alcohol and a C.sub.3 to C.sub.5 ether; and (e) recovering the
product.
13. The method of claim 1, comprising synthesizing a compound of
formula I, wherein R.sub.1 and R.sub.2 are not both hydrogen.
14. A method of synthesizing a
4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazo- lium salt comprising:
(a) reacting 4,5-dimethylthiazole with (IV), wherein X is a leaving
group, 11in a solvent having a dielectric constant at 20.degree. C.
of at least 30 but no more than 40; and (b) obtaining the
4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium product.
15. The method of claim 14, wherein the amount of solvent is
selected to dissolve compounds (a) and (b), but precipitate at
least a portion of the
4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium salt during the
reacting step.
16. The method of claim 15, wherein the amount of solvent is
selected to precipitate an amount of the
4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazol- ium salt equal to at
least 20% of the theoretical yield.
17. The method of claim 14, wherein the solvent is aprotic.
18. The method of claim 14, wherein the solvent is
acetonitrile.
19. The method of claim 14, wherein the reacting step is conducted
at elevated temperature maintained for at least 24 hours.
20. The method of claim 14, wherein the reacting step is conducted
at reflux
21. The method of claim 14, further comprising: (c)
re-crystallizing the product; (d) washing the re-crystallized
product by suspending it in a mixture of a C.sub.1 to C.sub.3
alcohol and a C.sub.3 to C.sub.5 ether; and (e) recovering the
product, wherein the alcohol/ether mixture, time of suspension, and
an election to conduct a total of one to three iterations of steps
(d) and (e) are selected to achieve at least 95% yield from the
crystallized product of step (c) and a purity of at least 99.5% by
isocratic, reversed-phase HPLC analysis monitored at 210 nm.
22. The method of claim 21, wherein the re-crystallized product is
suspended in a mixture of ethanol and methyl tert-butyl ether.
23. The method of claim 22, wherein the mixture is a 2:8 to 4:6
(v/v) mixture, respectively.
24. The method of claim 23, wherein the mixture is a 25:75 to 35:65
(v/v) mixture
25. The method of claim 14, further comprising: (c)
re-crystallizing the product; (d) washing the re-crystallized
product by suspending it in a 2:8 to 4:6 (v/v) mixture of a C.sub.1
to C.sub.3 alcohol and a C.sub.3 to C.sub.5 ether; and (e)
recovering the product.
Description
[0001] This application claims the priority of U.S. application
Ser. No. 60/192,867, filed Mar. 29, 2000.
[0002] The present invention relates to methods of synthesizing
certain thiazolium compounds.
[0003] In U.S. Pat. Nos. 5,656,261; 5,853,703; and 6,007,865
compounds were disclosed that are promising agents that can be used
in compositions and methods useful in treating a number of
indications. One mechanism of action contributing to these
treatments is believed to be inhibition and reversal of
nonenzymatic cross-linking (protein aging). These compounds can be
used in therapeutic applications where proteins in the body
deteriorate with age and as a consequence of diabetes.
[0004] Efficient syntheses for these compounds are desirable.
Described herein is a surprisingly effective synthesis of a certain
class of these compounds.
SUMMARY OF THE INVENTION
[0005] In one embodiment, the invention provides a method of
synthesizing a compound of formula I, 4
[0006] comprising: reacting a compound of formula II 5
[0007] wherein R.sub.1 and R.sub.2 are independently hydrogen,
hydroxy(C.sub.1-C.sub.2)alkyl, or (C.sub.1-C.sub.2)alkyl with, a
compound of the formula III 6
[0008] wherein R.sub.3, R.sub.4, and R.sub.5 are each independently
of each other hydrogen, (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)alkoxy, or halogen; and X is a leaving group. The
reaction is preferably conducted in a solvent having a dielectric
constant at 20.degree. C. of at least 30 but no more than 40
[0009] In another embodiment, the invention provides a method of
synthesizing a 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium salt
comprising: reacting 4,5-dimethylthiazole with (IV), wherein X is a
leaving group. 7
BRIEF DESCRIPTION OF DRAWINGS
[0010] FIGS. 1 and 2 show HPLC analyses of product made according
to the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0011] In accordance with the present invention, reaction and
purification conditions have been developed that allow the
preparation of N-alkyl thiazolium salts in high yield and of high
purity. Useful methods described, for example, relate to the
preparation of compounds of the formula I by reacting a compound of
formula II with a compound of the formula III wherein X is a
leaving group.
[0012] The solvent is selected to meet the characteristics
described above, allowing the improved yields that can be obtained
through the invention. Washing methods with appropriate solvents
can also be selected to yield N-alkyl thiazolium salts with
surprising purity from simple purification steps.
[0013] The leaving group referred to above preferably form a
pharmaceutically or biologically acceptable anion upon alkylation
of the thiazole moiety. Such anions include, for example, halides,
for example, chlorides and bromides, tosylates, methanesulfonates,
and mesitylenesulfonates. Other related leaving groups that are
used preferably are those that form stable, non-toxic, and
biologically or pharmaceutically acceptable salts upon alkylation
of the thiazole moiety.
[0014] The solvents referred to above are dipolar solvents. These
may include, for example, protic solvents, such as C.sub.2-C.sub.3
alcohols, and aprotic solvents, such as N-methylpyrrolidinone,
dimethylformamide, dimethylacetamide, dimethyl sulfoxide, and
acetonitrile. Solvents with dielectric constants at 20.degree. C.
above 30 but no more than 40 are preferred. Aprotic solvents are
also preferred.
[0015] Preferably a solvent is selected so that the product
thiazolium salt is only partially soluble. A solvent in which both
the reactants are soluble but in which the thiazolium salt product
is insoluble or only partially soluble is preferred. Acetonitrile
is a preferred solvent.
[0016] The reaction is conducted at elevated temperatures such as
80.degree. C. to 82.degree. C. A preferred solvent is one that has
a boiling point from 65.degree. C. to 110.degree. C. so that the
reaction temperature can be conveniently and consistently
maintained by refluxing the solvent. If the reaction mixture is
refluxed a condenser should be used during the reaction. Typically
the reaction is maintained at elevated temperatures for at least 24
hours. Preferably the temperature is maintained for at least 48 to
72 hours or from 80 to 100hours, e.g. about 90 or 90.5 hours. The
length of time will be dependent upon a number of factors,
including temperature, concentration, and solvent.
[0017] Typically molar ratios of substituted acetophenone
reagents/thiazoles combined in the reaction mixture are about 1:1
to 3:1. In some embodiments, ratios of about 1.5:1 to 2.5:1 (such
as about 2:1) are useful.
[0018] A preferred method of conducting the reaction uses an inert
atmosphere, for example using a blanket of nitrogen or argon gas.
Additionally, the reaction is stirred or agitated using, for
example, a mechanical stirring device.
[0019] Reaction progress can be followed by methods known to those
in the art including chromatographic methods such as thin layer
chromatography or HPLC. In solvents where the reaction begins to
precipitate during heating, a specialized procedure for sampling
the reaction mixture can be used. A slurry of the hot reaction
mixture is filtered and the precipitate and/or filtrate are
monitored by one of the chromatographic methods described above or,
the slurry is dissolved in a stronger solvent and analyzed
chromatographically. A preferred method is HPLC analysis when the
reaction solvent used does not absorb a detecting-interfering
amount of UV light at wavelengths where the products and reactants
are detected.
[0020] To isolate the reaction product, the reaction mixture is
cooled, for example, to a temperature of about 15.degree. C. to
30.degree. C., such as 22.degree. C. to 25.degree. C. Then, for
example, an ethereal solvent is added, and the reaction product
recovered by centrifugation or filtration. A preferred ethereal
solvent is methyl tert-butyl ether.
[0021] The purification of the reaction product can include a
recrystallization step. The process of selecting a suitable
recrystallization solvent(s) is known to those in the art.
Typically a solvent is chosen by consideration of a number of
factors including maximization of the amount of purified,
crystallized product when the crystallization mixture is cooled,
and satisfactory solubility of the crude reaction product with the
heated recrystallization solvent. Suitable recrystallization
solvents include, for example, C.sub.1-C.sub.3 alcohols. 1:1
2:1,
[0022] Further purification of the reaction product includes
washing steps. A suitable wash solution would optimally dissolve
maximal amounts of impurities while dissolving a minimal amount of
the desired reaction product. A wash solution could be prepared
from variable mixtures of two or more solvents. The wash solution
can be, for example, a mixture of a C.sub.1-C.sub.3 alcohol and a
C.sub.3-C.sub.5 ether. A preferred wash solution is a mixture of
ethanol and methyl tert-butyl ether. The mixture of ethanol and
ether is preferably a 2:8 to 4:6 (v/v) mixture and more preferably,
a 25:75 to 35:65 (v/v) mixture.
[0023] The washing step can be performed after recovery of the
reaction product on a filter. In addition, the washing cycle can be
repeated, for example to achieve a higher purity of the product.
Preferably the purity of the reaction product from the washing
steps is at least 99.5% by isocratic reversed-phase HPLC analysis
at 210 nm, preferably at least 99.7% or 99.8%. The washing step can
further comprise suspending the reaction product in the washing
solvent, agitating the resulting slurry, and recovering the product
by filtration. Typically, the slurry is agitated at about
20.degree. C. to 25.degree. C.
[0024] The methods for isolation of the product described in the
invention include drying steps. The compound can be, for example,
dried at room temperature under vacuum, on trays lined with dryer
paper.
[0025] Analytical methods for determining the purity of reaction
product are known in the art. These include spectroscopic methods,
for example, NMR spectroscopy and chromatographic methods. A
preferred method of determining the purity of the product
thiazolium salt is by application of HPLC techniques. While
satisfactory analytical HPLC can be performed under a variety of
conditions, preferred conditions include using a column with
reversed phase packing such as 5.mu. ODS-2 (C-18) packing. For
example, the 4.6.times.250 mm 5.mu. ODS-2 column from Metachem
Technologies (Torrance, Calif.). Typically an isocratic solvent
system is used to elute the sample, for example, a mobile phase
containing 65% of an aqueous buffer of 10 mM 1-nonane sulfonic acid
sodium salt and 50 mM sodium phosphate monobasic and 35%
acetonitrile. The HPLC chromatogram is generated, for example,
using a UV detector. Typical settings for analysis of the product
thiazolium salt include monitoring at 210 nm or 252 nm.
[0026] Preferably, HPLC data is collected with data sampling at
least as frequent as every 0.1 second periods. Preferably, the data
is zeroed against a baseline run of the HPLC apparatus. Sensitivity
or peak detection threshold is preferably set to a high sensitivity
value that nonetheless allows data collection without spurious
collection of detector or electronic noise. For example, using
Rainin Dynamax R software (version 1.4) to collect the data, and
Rainin Dynamax Mode UV-1 UV/visible variable wavelength detector,
minimum peak detection sensitivity can be set at 10-50
millivolt/second or lower.
[0027] FIG. 1 shows an analysis of a batch of
4,5-dimethyl-3-(2-oxo-2-phen- ylethyl)-thiazolium chloride as
analyzed by a gradient HPLC method that uses a 25 to 50%
acetonitrile gradient. FIG. 2 shows an isocratic analysis (35%
acetonitrile, v/v). HPLC chromatographs were developed in 50 mM
NaH.sub.2PO.sub.4, 10 mM 1-nonane sulfonic acid Detection was at
210 nm.
[0028] The yield of the product from the above conditions is high
(e.g. 70% overall, or higher). The product can be obtained at high
purity using the methods here described (>99.5% as determined by
HPLC). Additionally, the process is convenient for preparing
thiazolium salts on a commercial scale.
[0029] The following example further illustrate the present
invention, but of course, should not be construed as in any way
limiting its scope.
EXAMPLE 1
[0030] Preparation of
4,5-Dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride A reactor
equipped with an agitator and a condenser was charged with 37.47 kg
of acetonitrile, and purged with nitrogen. A blanket of nitrogen
was maintained during the reaction. Agitation was started and 9.52
kg of 4,5-dimethylthiazole (84.1 mmol) and 13.00 kg of
2-chloroacetophenone (84.1 mmol) were added into the reactor. The
mixture was agitated and heated to reflux (81.degree. C.).
Refluxing was maintained at this temperature for about 96.5 hours.
The reaction was monitored by HPLC for the presence of
4,5-dimethyl-3-(2-oxo-2-phenylethyl- )-thiazolium chloride in the
refluxate. The product precipitated out of the hot reaction mixture
during reflux. After 3 days a sample of hot reaction slurry was
filtered, and washed with a mixture of absolute ethanol and methyl
tert-butyl ether (3:7). An HPLC analysis of this sample showed no
detectable amounts of starting materials.
[0031] The reaction was cooled to 20.degree. C. to 25.degree. C.
and 33.7 kg of methyl tert-butyl ether was added. The batch was
agitated at 20.degree. C. to 25.degree. C. for about 3 hours. Part
of the mixture was isolated in the centrifuge; the remaining
product was agitated overnight and was isolated by filtering
through a large buchner funnel fitted with Whatman # 1 filter
paper. The product from the centrifuge was transferred to the top
of the cake in the buchner funnel. The reactor (R-2) was rinsed
with 20 L of methyl tert-butyl ether onto the product cake. The
filtered cake was washed three times with a wash solution
containing a mixture of 4.17 kg of absolute ethanol and 9.74 kg of
methyl tert-butyl ether. The wet solid (20.07 kg) was transferred
to the drying trays. The product was evenly distributed on the
trays and dried at room temperature under vacuum (25.6" Hg) for 18
hours. The dry weight of the
4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride was 17.99
kg.
[0032] Crude 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium
chloride was recrystallized by charging the crude
4,5-dimethyl-3-(2-oxo-2-phenylethyl)- -thiazolium chloride into a
reactor equipped with a condenser and an agitator. Absolute ethanol
37.19 kg was added and agitation was started. The reactor was
purged with nitrogen and a nitrogen blanket was maintained during
the processing. The mixture was heated to gentle reflux and
maintained at 78.degree. C. until a complete solution was attained.
From the bottom outlet of the reactor to the inlet of another
reactor, a 0.5 micron in-line cartridge filter was set up using an
appropriate pump. When the batch was in solution, the filter
cartridge, pump, and lines were preheated with the hot absolute
ethanol in the first reactor. The batch was filtered into the new
reactor. Absolute ethanol (4.2 kg) was used to rinse the first
reactor into the reactor containing the filtrate. The batch was
cooled to 20.degree. C. to 25.degree. C. and agitated at this
temperature overnight. The product was filtered through a large
Buchner funnel fitted with a Whatman No. 1 filter paper. The
filtered cake was washed with a wash solution containing a mixture
of 5.80 kg of absolute ethanol and 13.52 kg of methyl tert-butyl
ether. The wet 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazoliurn
chloride (14.36 kg) was transferred in the trays lined with dryer
paper. The product was distributed evenly on the trays.
4,5-Dimethyl-3-(2-oxo-2-phenylethyl)-thi- azolium chloride was
dried at room temperature under vacuum (25.9" Hg) about 23 hours to
a constant weight (12.21 kg, 71.65%) (Lot A).
4,5-Dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride (Lot A)
was further purified through washing. Methyl tert-butyl ether 18.9
kg and absolute ethanol 8.0 kg were added to a reactor equipped
with a condenser and an agitator. The reactor was purged with
nitrogen and a nitrogen blanket was maintained during the
processing. 4,5-Dimethyl-3-(2-oxo-2-phe- nylethyl)-thiazolium
chloride (Lot. A) 11.9 kg was charged into the reactor and the
agitator started. The slurry was stirred at 20.degree. C. to
25.degree. C. for about 30 minutes. The product was filtered
through a large buchner funnel fitted with a Whatman No. 1 filter
paper. The filtered cake was washed with a wash solution containing
a mixture of 1.3 kg of absolute ethanol and 3.2 kg of methyl
tert-butyl ether. The wet
4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride (13.4 kg)
was transferred to the trays lined with dryer paper. The product
was distributed evenly on the trays.
4,5-Dimethyl-3-(2-oxo-2-phenylethyl)-thi- azolium chloride was
dried at room temperature under vacuum (25.9" Hg) about 2 hours to
a constant weight. The dryer was unloaded into a tared,
polyethylene bag-lined drum or pail. (11.8 kg, 99.2% from Lot No.
A; 70% overall yield (Lot No. B).
[0033] All publications and references, including but not limited
to patents and patent applications, cited in this specification are
herein incorporated by reference in their entirety as if each
individual publication or reference were specifically and
individually indicated to be incorporated by reference herein as
being fully set forth. Any patent application to which this
application claims priority is also incorporated by reference
herein in its entirety in the manner described above for
publications and references.
[0034] While this invention has been described with an emphasis
upon preferred embodiments, it will be obvious to those of ordinary
skill in the art that variations in the preferred devices and
methods may be used and that it is intended that the invention may
be practiced otherwise than as specifically described herein.
Accordingly, this invention includes all modifications encompassed
within the spirit and scope of the invention as defined by the
claims that follow.
* * * * *